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Background <p>Dectin-1, a key innate immune receptor, plays a critical role in cellular responses and is implicated in chronic inflammation and metabolic syndromes. This study addresses a pivotal gap in elucidating the regulatory mechanism governing Dectin-1 expressionin obesity and diabetes, hypothesizing that hyperglycemia and TNF-α synergistically upregulate Dectin-1 in adipose tissue (AT), thereby exacerbating inflammatory responses and contributing to metabolic dysfunction.</p> Methods <p>The study included 95 overweight and obese Kuwaiti individuals, categorized into prediabetic (HbA1c &lt; 6.5%) and diabetic (HbA1c ≥ 6.5%) groups. Anthropometric and clinical measurements were recorded. AT biopsies were obtained for RNA extraction and immunohistochemistry. Pre-adipocytes from lean and obese individuals were cultured, differentiated into adipocytes, and treated with TNF-α under normal or high-glucose conditions to assess Dectin-1 expression. Chromatin immunoprecipitation (ChIP) assays analyzed NF-κB binding to the Dectin-1 promoter. Wildtype and TNF-α-/- mice were used to evaluate TNF-α’s effect on Dectin-1 expression in AT.</p> Results <p>Our data demonstrate that hyperglycemic obesity significantly induces Dectin-1 expression in AT through the TNF-α/NF-κB signaling pathway. In a cohort of 95 obese individuals, subdivided into prediabetics (HbA1c &lt; 6.5%, <i>n</i> = 49) and diabetics (HbA1c ≥ 6.5%, <i>n</i> = 46), a strong positive correlation was observed between AT Dectin-1 transcripts and plasma HbA1c levels exclusively in diabetic participants, underscoring the specificity of Dectin-1 upregulation in hyperglycemic conditions. Elevated Dectin-1 expression was consistently associated to increased inflammation markers. Immunohistochemical analysis revealed co-localization and concurrent upregulation of Dectin-1 and TNF-α proteins in hyperglycemic AT. Functional assays in TNF-α deficient mice and human adipocytes further validated that TNF-α and hyperglycemia act cooperatively to regulate Dectin-1 expression. Mechanistically, we demonstrated that NF-κB directly binds to the Dectin-1 promoter, mediating its transcriptional activation in response to glucose and TNF-α.</p> Conclusion <p>This study significantly advances the understanding of upregulation Dectin-1 in metabolic inflammation, filling a crucial niche in diabetes research and suggesting new therapeutic targets for obesity-related metabolic disorders.</p>

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TNF-α/NF-κB mediated upregulation of Dectin-1 in hyperglycemic obesity: implications for metabolic inflammation and diabetes

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月23日

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  • Ashraf Al Madhoun,
  • Dania Haddad,
  • Shihab Kochumon,
  • Reeby Thomas,
  • Lavina Miranda,
  • Preethi George,
  • Nermeen Abu-Khalaf,
  • Fahd Al-Mulla,
  • Rasheed Ahmad

摘要

Background

Dectin-1, a key innate immune receptor, plays a critical role in cellular responses and is implicated in chronic inflammation and metabolic syndromes. This study addresses a pivotal gap in elucidating the regulatory mechanism governing Dectin-1 expressionin obesity and diabetes, hypothesizing that hyperglycemia and TNF-α synergistically upregulate Dectin-1 in adipose tissue (AT), thereby exacerbating inflammatory responses and contributing to metabolic dysfunction.

Methods

The study included 95 overweight and obese Kuwaiti individuals, categorized into prediabetic (HbA1c < 6.5%) and diabetic (HbA1c ≥ 6.5%) groups. Anthropometric and clinical measurements were recorded. AT biopsies were obtained for RNA extraction and immunohistochemistry. Pre-adipocytes from lean and obese individuals were cultured, differentiated into adipocytes, and treated with TNF-α under normal or high-glucose conditions to assess Dectin-1 expression. Chromatin immunoprecipitation (ChIP) assays analyzed NF-κB binding to the Dectin-1 promoter. Wildtype and TNF-α-/- mice were used to evaluate TNF-α’s effect on Dectin-1 expression in AT.

Results

Our data demonstrate that hyperglycemic obesity significantly induces Dectin-1 expression in AT through the TNF-α/NF-κB signaling pathway. In a cohort of 95 obese individuals, subdivided into prediabetics (HbA1c < 6.5%, n = 49) and diabetics (HbA1c ≥ 6.5%, n = 46), a strong positive correlation was observed between AT Dectin-1 transcripts and plasma HbA1c levels exclusively in diabetic participants, underscoring the specificity of Dectin-1 upregulation in hyperglycemic conditions. Elevated Dectin-1 expression was consistently associated to increased inflammation markers. Immunohistochemical analysis revealed co-localization and concurrent upregulation of Dectin-1 and TNF-α proteins in hyperglycemic AT. Functional assays in TNF-α deficient mice and human adipocytes further validated that TNF-α and hyperglycemia act cooperatively to regulate Dectin-1 expression. Mechanistically, we demonstrated that NF-κB directly binds to the Dectin-1 promoter, mediating its transcriptional activation in response to glucose and TNF-α.

Conclusion

This study significantly advances the understanding of upregulation Dectin-1 in metabolic inflammation, filling a crucial niche in diabetes research and suggesting new therapeutic targets for obesity-related metabolic disorders.